The long-term objective of this proposal is to design a novel immunomodulatory therapy for tolerance induction for treatment of autoimmune (type 1) diabetes. The specific aim of the proposal is to test a transforming growth factor-beta 1 (TGF-beta1) based methodology for inducing islet antigen-specific regulatory T cells that are capable of transferring self-tolerance in the mouse model of human type 1 diabetes. The potential findings from this research proposal would have significant implications in treatment of patients with type 1 diabetes. The candidate will perform the proposed studies using the non-obese diabetic (NOD) mouse model of human type 1 diabetes. The step-wise approach for pursuing these goals will be: (1) to induce TGF-beta1 dependent islet antigen-specific regulatory T cells from a polyclonal naive T cell population, using dendritic cells for selecting antigen specificities;(2) to test the therapeutic efficacy of the TGF-beta 1-induced regulatory T cells in reverting established diabetes in the NOD mouse;and (3) to determine the potential endogenous source(s) of TGF-beta1, particularly among dendritic cell subsets which are newly recognized to play an important role in tolerance induction. Current treatment for human type 1 diabetes requires life-long insulin therapy or long-term immunosuppression for transplantation, both of which have significant risks and unwanted side-effects. Successful completion of the proposed project will help us design immunomodulatory therapies that specifically target the autoimmune process for treatment of this devastating disease. In addition to having intrinsic research importance, the proposed research contains the necessary components of serving as a suitable vehicle for learning the methodology, theories, and conceptualizations necessary for transition of the candidate to an independent investigator. Together with the conducive environment at Northwestern University Feinberg School of Medicine, the dedication and commitment of the candidate's sponsor and co-sponsors to the candidate's career development, and the candidate's accomplished research background, this proposed research and training would provide the central force for bringing these elements together and ultimately contribute to fulfillment of the candidate's career goal.